Age-related macular degeneration (AMD) is a prevalent retinal disorder which will impact approximately 10% of the aging Veteran and general U.S. population. The most devastating forms of AMD are those that impact the central retina which supports high acuity vision needed for reading, driving and other activities of daily life. Therapies are available for the most sever form of `wet' AMD where abnormal blood vessel formation leads to detachment of the central retina, but these are not always effective. Therapies are not, however, available for the more prevalent form of `dry' AMD in which the retinal pigment epithelial (RPE) cells that support the function of light-sensitive rod and cone photoreceptors are lost. When these RPE cells are located in the central retina, vision loss is severe and permanent. AMD is a complex genetic condition, and the last decade has seen important advances in the identification of AMD susceptibility genes. These advances were made primarily based on a large-scale study of affected patients and unaffected controls of European heritage recruited across multiple institutions and clinics. While an excellent start, it is not clear that these advances will pertai to patients of other ethnic heritage, especially in view of the distinct clinical presentations of AMD patients of European as compared to African descent. A major purpose of this project is to determine whether the AMD susceptibility genes identified to date are shared in African- Americans. This question is of particular importance as the recent advances in AMD genetics are being used to develop new therapeutics to slow or halt vision loss in the more prevalent forms of AMD. The Million Veteran Program (MVP) has enrolled more than 27,000 well- characterized AA Veterans, whose data will allow us to answer this question in Aim 1. In addition, Aim 1 will use the European-American MVP cohort to support an independent evaluation of the AMD susceptibility genes that have been identified to date. The final issue addressed in Aim 1 of the present application is whether additional AMD genes might be discovered. The sheer scale of MVP provides the statistical power to address that question. Aim 2 will conduct fine-mapping studies of the gene loci identified in Aim 1, to better understand the underlying gene defect. Aim 3 will determine whether relationships exist between AMD status, AMD genetic markers and clinical biomarkers with a special focus on lipid profiles. This project will have important influences on the field of AMD genetics, the development of AMD therapeutics and will help to ensure that these developments are applicable to Veterans and U.S. citizens of all ethnic heritages.